Selective oxidation of carbohydrates

Abstract

The invention relates to the field of carbohydrate chemistry. Provided is a process for the regioselective oxidation of a single secondary hydroxy function of a carbohydrate substrate comprising two or more secondary hydroxy functions, comprising contacting the carbohydrate substrate in a solvent in the presence of a transition metal catalyst complex with an oxidizing agent to yield a mono-oxidized carbohydrate.

Claims

1. A process for the regioselective oxidation of a single secondary hydroxy function of a carbohydrate substrate comprising two or more secondary hydroxy functions, wherein the carbohydrate substrate is a neamine-based aminoglycoside antibiotic selected from the group consisting of neomycin, neamin, amikacin, paromomycin, ribostamycin, kanamycin, framycetin, isepamicin, and derivatives thereof, and wherein the single secondary hydroxyl function is the C3 hydroxyl of ring I of the neamine-backbone, comprising contacting the carbohydrate substrate in a solvent in the presence of a transition metal catalyst complex with an oxidizing agent to yield a mono-oxidized carbohydrate, and wherein the catalyst complex comprises at least one transition metal atom selected from palladium, ruthenium, copper, manganese and iron and one or more ligands comprising at least one nitrogen atom.

2. A process according to claim 1, wherein the transition metal catalyst complex comprises palladium.

3. A process according to claim 2, wherein the transition metal catalyst complex comprises at least one palladium atom and one or more ligands comprising at least one nitrogen atom.

4. A process according to claim 3, wherein the transition metal catalyst complex is a palladium phenanthroline or a palladium bis(aryl)acenapthenequinonediimine (BIAN) complex in which the phenanthroline or the BIAN ligand is optionally substituted.

5. A process according to claim 1, wherein the transition metal catalyst complex is used in a molar ratio of 0.01-10 mol % with respect to the carbohydrate substrate.

6. A process according to claim 1, wherein the oxidizing agent is selected from the group consisting of a quinone, oxygen, air, peroxide and hydroperoxide.

7. A process according to claim 1, wherein the process is performed at a temperature between 0-100 C.

8. A process according to claim 1, wherein the oxidation reaction is performed in solvent containing water, DMSO, DMF, THF, dioxane, acetonitril, HMPA, NMP, or any mixture thereof.

9. Process according to claim 8, wherein the reaction is performed in a mixture of acetonitrile/water in a ratio of 4:1 to 20:1 (v/v), in DMSO, in a mixture of dioxane/water in a ratio of 4:1 to 20:1 (v/v), or dioxane/DMSO in a ratio of 4:1 to 20:1 (v/v).

10. Process according to claim 1, wherein the carbohydrate substrate does not carry any protecting groups on the secondary hydroxyl groups.

11. Process according to claim 1, wherein the mono-oxidized carbohydrate is subjected to a further derivatization reaction.

12. Process according to claim 11, wherein said further derivatization reaction comprises reduction, reductive amination, acetalisation, diazotation, hydrocyanation, imination, oximation, hydrazination, de-oxygenation, alkylation, or any combination thereof.

Description

EXPERIMENTAL SECTION

Example 1

Synthesis of Oxo-glucopyranosides

(1) General Procedure a (Acetonitrile/Water as Solvent)

(2) Methyl glycoside (4 mmol, 1.0 eq) and 2,6-dichlorobenzoquinone (12 mmol, 3.0 eq) were suspended in acetonitrile/de-ionized water (10:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (0.1 mmol, 2.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by TLC (DCM/MeOH 5:1). Toluene (50 mL) was added and the mixture was extracted twice with water (7 mL). The combined water layers were washed once with ethyl ether (35 mL), filtered and concentrated in vacuo to give the pure keto-sugar.

(3) ##STR00002##
General Procedure B (DMSO as Solvent)

(4) Methyl glycoside (0.84 mmol, 1.0 eq) and 2,6-dichlorobenzoquinone (2.5 mmol, 3.0 eq) were dissolved in DMSO (0.3-0.9 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (0.021 mmol, 2.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by NMR-spectroscopy. 10 mL water was added, the mixture was filtered and the precipitates were washed with water (32 mL). The water layer was passed over a charcoal column (10 g of charcoal). The charcoal column was washed with 4 column volumes of water and subsequently the product was eluted with water/acetonitrile 3:1 (3 column volumes). The crude product was purified by silica column chromatography (automated, the crude product was coated on charcoal, eluent: DCM/acetone/MeOH/water mixtures).

(5) General Procedure C (Dioxane/Water as Solvent and 2,6-dichlorobenzoquinone as Oxidant)

(6) Methyl glycoside (0.15 mmol, 1.0 eq) and 2,6-dichlorobenzoquinone (0.45 mmol, 3.0 eq) were suspended in dioxane/de-ionized water (5:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (0.1 mmol, 2.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by TLC (DCM/MeOH 5:1). Toluene (2 mL) was added and the mixture was extracted twice with water (0.26 mL). The combined water layers were washed once with ethyl ether (1.3 mL), filtered and concentrated in vacuo to give the pure keto-sugar.

(7) General Procedure D (Dioxane/DMSO as Solvent and 2,6-dichlorobenzoquinone as Oxidant)

(8) Methyl glycoside (0.15 mmol, 1.0 eq) and 2,6-dichlorobenzoquinone (0.45 mmol, 3.0 eq) were suspended in dioxane/DMSO (10:1 or 20:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (0.1 mmol, 2.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by TLC (DCM/MeOH 5:1). Toluene (2 mL) was added and the mixture was extracted twice with water (0.26 mL). The combined water layers were washed once with ethyl ether (1.3 mL), filtered and concentrated in vacuo to give the pure keto-sugar (contains still DMSO.

(9) General Procedure E (Dioxane/Water as Solvent and Benzoquinone as Oxidant)

(10) Methyl glycoside (0.25 mmol, 1.0 eq) and benzoquinone (0.75 mmol, 3.0 eq) were suspended in dioxane/de-ionized water (5:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (1.25 mol, 0.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by TLC (DCM/MeOH 5:1). Toluene (2 mL) was added and the mixture was extracted twice with water (0.26 mL). The combined water layers were washed once with ethyl ether (1.3 mL), filtered and concentrated in vacuo to give the pure keto-sugar.

(11) General Procedure F (Dioxane/DMSO as Solvent and Benzoquinone as Oxidant)

(12) Methyl glycoside (0.25 mmol, 1.0 eq) and 2,6-dichlorobenzoquinone (0.75 mmol, 3.0 eq) were suspended in dioxane/DMSO (10:1 or 20:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (1.25 mol, 0.5 mol %) was added and the mixture was stirred at rt until the reaction was finished, as indicated by TLC (DCM/MeOH 5:1). Toluene (2 mL) was added and the mixture was extracted twice with water (0.26 mL). The combined water layers were washed once with ethyl ether (1.3 mL), filtered and concentrated in vacuo to give the pure keto-sugar (contains still DMSO.

Example 2

Synthesis of Methyl--D-ribo-hexapyranoside-3-ulose

(13) ##STR00003##

(14) Methyl--glucopyranoside (777 mg, 4.0 mmol, 1.0 eq) was oxidized according to general procedure A using 2,6-dichloro-1,4-benzoquinone (2.12 g, 12.0 mmol, 3.0 eq.) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (105 mg, 2.5 mol %) in acetonitrile/water (13.4 mL, 10:1, 0.3 M in substrate) within 3 h. Methyl--D-ribo-hexapyranosid-3-ulose (751 mg, 3.9 mmol) was isolated in 98% yield as a dark brown solid. .sup.1H NMR.sup.[1] (400 MHz, 298 K, DMSO-d.sub.6): =4.95 (d, J=4.2 Hz, 1H), 4.29 (dd, J=4.2, 1.5 Hz, 1H), 4.07 (dd, J=9.8, 1.4 Hz, 1H), 3.69 (dd, J=11.9, 1.9 Hz, 1H), 3.59 (dd, J=11.9, 4.9 Hz, 1H), 3.46 (ddd, J=9.7, 4.9, 1.8 Hz, 1H), 3.26 (s, 3H). .sup.13C NMR (50 MHz, DMSO-d.sub.6): =206.1, 102.2, 75.4, 74.6, 71.9, 60.7, 54.4. HRMS (ESI) calculated for C.sub.7H.sub.12O.sub.6Na ([M+Na].sup.+): 215.0526. found: 215.0523 IR .sub.max/cm.sup.1: 3436 (OH), 2947 (CH), 1736 (CO), 1031 (CO).

Example 3

Synthesis of Methyl--D-ribo-hexapyranoside-3-ulose

(15) ##STR00004##

(16) Methyl--glucopyranoside (777 mg, 4.0 mmol, 1.0 eq.) was oxidized according to general procedure A using 2,6-dichloro-1,4-benzoquinone (2.12 g, 12.0 mmol, 3.0 eq) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (105 mg, 2.5 mol %) in acetonitrile/water (13.4 mL, 10:1, 0.3 M in substrate) within 5 h. Methyl--D-ribo-hexapyranosid-3-ulose (686 mg, 3.6 mmol) was isolated in 89% yield as a dark brown solid. .sup.1H NMR.sup.[2][3] (400 MHz, 298 K, DMSO-d.sub.6): =4.20 (d, J=8.0 Hz, 1H), 4.05 (dd, J=10.2, 1.6 Hz, 1H), 3.97 (dd, J=8.0, 1.6 Hz, 1H), 3.73 (dd, J=11.9, 1.7 Hz, 1H), 3.58 (dd, J=12.0, 5.1 Hz, 1H), 3.45 (s, 3H), 3.21 (ddd, J=10.2, 5.1, 1.7 Hz, 1H). .sup.13C NMR (50 MHz, 298 K, DMSO-d.sub.6): =206.3, 104.8, 76.6, 76.6, 72.2, 60.8, 56.2. HRMS (ESI) calculated for C.sub.7H.sub.12O.sub.6Na ([M+Na].sup.+): 215.0526. found: 215.0523 IR .sub.max/cm.sup.1: 3382 (OH), 2953 (CH), 1738 (CO), 1036 (CO).

Example 4

Synthesis of Methyl-2-(acetylamino)-2-deoxy--D-ribo-hexapyranosid-3-ulose

(17) ##STR00005##

(18) Methyl-N-acetyl-glucosamine-pyranoside (941 mg, 4 mmol, 1.0 eq) was oxidized according to general procedure A using 2,6-dichloro-1,4-benzoquinone (2.12 g, 12.0 mmol, 3.0 eq) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (105 mg, 2.5 mol %) in acetonitrile/water (13.4 mL, 10:1, 0.3 M in substrate) within 4 h. Methyl-2-(acetylamino)-2-deoxy--D-ribo-hexapyranosid-3-ulose (792 mg, 3.4 mmol) was isolated in 85% as a dark brown solid. .sup.1H NMR.sup.[4] (400 MHz, 298 K, DMSO-d.sub.6): =8.02 (d, J=8.2 Hz, 1H), 5.49 (d, J=6.0 Hz, 1H), 4.98 (d, J=4.0 Hz, 1H), 4.84 (s, 1H), 4.77 (dd, J=7.9, 3.7 Hz, 1H), 4.17 (dd, J=9.5, 5.5 Hz, 1H), 3.71 (d, J=11.7 Hz, 1H), 3.66-3.57 (m, 1H), 3.57-3.49 (m, 1H), 3.26 (s, 3H), 1.91 (s, 3H). .sup.13C NMR (50 MHz, DMSO-d.sub.6): =203.0, 169.7, 100.6, 75.6, 72.2, 60.7, 58.6, 54.5, 22.2. HRMS (ESI) calculated for C.sub.9H.sub.15NO.sub.6H ([M+H].sup.+): 234.0972. found: 234.0972, C.sub.9H.sub.15O.sub.6Na ([M+Na].sup.+): 256.0792. found: 256.0790 IR .sub.max/cm.sup.1: 3296 (OH), 2878 (CH), 1734 (CO), 1035 (CO).

Example 5

Synthesis of (6-O-tert-butyl-diphenylsilyl)-methyl--D-ribo-hexapyranoside-3-ulose (OxTBDPS-MGlc)

(19) ##STR00006##

(20) Methyl-C6-TBDPS--glucopyranoside (364 mg, 0.84 mmol, 1.0 eq) and 2,6-dichloro-1,4-benzoquinone (447 mg, 2.53 mmol, 3.0 eq) were dissolved in DMSO (0.93 mL, 0.9 M) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (22 mg, 2.5 mol %) was added. The mixture was stirred at rt for 30 min. The reaction was quenched by adding water (12 mL) and the resulting precipitate was decanted. The precipitate was dissolved in MeOH/Et.sub.2O to transfer it. Concentration of the dissolved precipitate in vacuo gave 774 mg of crude product, which was purified by silica column chromatography (eluent: gradient of acetone/MeOH 1:1 in DCM 0%-3%). 239 mg of pure (6-O-tert-butyl-diphenylsilyl)-methyl--D-ribo-hexapyranoside-3-ulose (0.56 mmol, 66%) was isolated as a white foam. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.82-7.64 (m, 4H), 7.54-7.28 (m, 6H), 5.08 (d, J=4.3 Hz, 1H), 4.40 (dd, J=4.3, 1.4 Hz, 1H), 4.34 (dd, J=9.8, 1.4 Hz, 1H), 4.00 (d, J=3.3 Hz, 2H), 3.74 (dt, J=9.7, 3.3 Hz, 1H), 3.40 (s, 3H), 1.07 (s, 9H). .sup.13C NMR (101 MHz, CD.sub.3OD): =207.2, 136.9, 136.9, 134.8, 134.7, 131.0, 131.0, 128.9, 103.8, 77.0, 76.3, 73.6, 64.8, 55.8, 27.4, 20.3. HRMS (ESI) calculated for C.sub.23H.sub.30O.sub.6SiNa ([M+Na].sup.+): 453.1704. found: 453.1643.

Example 6

Synthesis of (6-O-benzoyl)-methyl--D-ribo-hexapyranoside-3-ulose (OxBzMGlc)

(21) ##STR00007##

(22) (6-O-benzoyl)-methyl--D-glucopyranoside (251 mg, 0.84 mmol, 1.0 eq) and 2,6-dichloro-1,4-benzoquinone (447 mg, 2.53 mmol, 3.0 eq) were dissolved in DMSO (0.93 mL, 0.9 M) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (22 mg, 2.5 mol %) was added. The mixture was stirred at rt for 1 h. The reaction was quenched by adding water (10 mL), the resulting precipitate was filtered and the filter was washed with water (110 mL, 15 mL). The water layer was passed over a charcoal column (10 g charcoal). The charcoal column was washed with 4.5 column volumes of water, 3 column volumes of water/acetonitrile (3:1) and subsequently the product was eluted with 3 column volumes of DCM/acetone/MeOH/water (56/20/20/4) which gave 409 mg of crude product. The crude product was purified by silica column chromatography (automated, eluent: gradient of DCM/MeOH 0-10%). 113 mg of pure (6-O-benzoyl)-methyl--D-ribo-hexapyranoside-3-ulose (45%) was isolated as a white foam.

(23) .sup.1H NMR (400 MHz, CD.sub.3OD): =8.09-8.03 (m, 2H), 7.65-7.58 (m, 1H), 7.52-7.46 (m, 2H), 5.08 (d, J=4.3 Hz, 1H), 4.72 (dd, J=11.9, 2.2 Hz, 1H), 4.57 (dd, J=11.9, 5.7 Hz, 1H), 4.48 (dd, J=4.3, 1.5 Hz, 1H), 4.34 (dd, J=10.0, 1.4 Hz, 1H), 3.99 (ddd, J=9.9, 5.6, 2.1 Hz, 1H), 3.42 (s, 3H). .sup.13C NMR (101 MHz, CD.sub.3OD): =206.3, 167.8, 134.6, 131.3, 130.7, 129.8, 103.8, 76.2, 74.2, 74.0, 65.3, 55.9. HRMS (ESI) calculated for C.sub.14H.sub.16O.sub.7Na ([M+Na].sup.+): 319.0788. found: 319.0739.

Example 7

Synthesis of Methyl--3-ketomaltoside

(24) ##STR00008##

(25) Methyl--maltoside (300 mg, 0.84 mmol, 1.0 eq) was oxidized according to general procedure B using 2,6-dichloro-1,4-benzoquinone (447 mg, 2.53 mmol, 3.0 eq) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (22 mg, 2.5 mol %) in DMSO (0.94 mL, 0.9 M) within 3.5 h (reaction stopped at 87% conversion). 10 mL water was added, the mixture was filtered and the precipitates were washed with water (42 mL). The water layer was passed over a charcoal column (10 g of charcoal). The charcoal column was washed with 4 column volumes of water and subsequently the product was eluted with water/acetonitrile 3:1 (2 column volumes). 308 mg of product, 70% pure according to NMR, was isolated after concentration in vacuo. 125 mg of pure methyl--ketomaltoside (0.25 mmol, 42%) was isolated after column chromatography (eluent: DCM/acetone/MeOH/water 56:20:20:4) along with 20 mg of mixed fractions. .sup.1H NMR (400 MHz, CD.sub.3OD): =5.62 (d, J=4.5 Hz, 1H), 4.45 (dd, J=4.5, 1.6 Hz, 1H), 4.25 (dd, J=9.6, 1.5 Hz, 1H), 4.15 (d, J=7.8 Hz, 1H), 3.92-3.70 (m, 5H), 3.60-3.55 (m, 2H), 3.51 (s, 3H), 3.34-3.31 (m, 1H), 3.21-3.15 (m, 1H). .sup.13C NMR (101 MHz, CD.sub.3OD): =207.2, 105.4, 104.8, 80.6, 78.0, 77.7, 76.6, 76.4, 74.8, 73.4, 62.6, 62.1, 57.5. HRMS (ESI) calculated for C.sub.13H.sub.22O.sub.11Na ([M+Na].sup.+): 377.1054. found: 377.1048.

Example 8

Synthesis of Methyl--3-ketocellobioside

(26) ##STR00009##

(27) Methyl--cellobioside (300 mg, 0.84 mmol, 1.0 eq) was oxidized according to general procedure B using 2,6-dichloro-1,4-benzoquinone (447 mg, 2.53 mmol, 3.0 eq) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (22 mg, 2.5 mol %) in DMSO (0.94 mL, 0.9 M) within 2 h. 88 mg of pure methyl--3-ketocellobioside (0.25 mmol, 30%) was isolated after column chromatography (eluent: DCM/acetone/MeOH/water 56:20:20:4) along with 38 mg (13%) of starting material. .sup.1H NMR (400 MHz, CD.sub.3OD): =4.55 (d, J=7.9 Hz, 1H), 4.25 (dd, J=10.2, 1.5 Hz, 1H), 4.22 (d, J=7.8 Hz, 1H), 4.19 (dd, J=8.0, 1.6 Hz, 1H), 3.95 (dd, J=12.1, 2.0 Hz, 1H), 3.88 (qd, J=12.2, 3.1 Hz, 3H), 3.78 (dd, J=12.1, 5.0 Hz, 1H), 3.66 (t, J=9.2 Hz, 1H), 3.56 (t, J=9.0 Hz, 1H), 3.53 (s, 3H), 3.44-3.34 (m, 2H), 3.24 (dd, J=9.0, 8.0 Hz, 1H). .sup.13C NMR (101 MHz, CD.sub.3OD): =206.8, 105.9, 105.4, 80.5, 78.4, 78.4, 76.6, 76.53, 75.0, 73.6, 62.5, 61.6, 57.5.

(28) HRMS (ESI) calculated for C.sub.13H.sub.22O.sub.11Na ([M+Na].sup.+): 377.1054. found: 377.1002.

Example 9

Comparison Between Various Oxidizing Agents

(29) Oxygen (MeCN/Water as Solvent)

(30) Methyl--glucopyranoside (100 mg, 0.52 mmol, 1.0 eq) was suspended in acetonitrile/de-ionized water (10:1, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (13 mg, 13 mol, 2.5 mol %) was added and the mixture was stirred at room temperature (rt) under oxygen atmosphere (1 atm). The reaction stopped after 43 h at 45% conversion as indicated by .sup.1H-NMR.

(31) Oxygen (DMSO as Solvent)

(32) Methyl--glucopyranoside (100 mg, 0.52 mmol, 1.0 eq) was dissolved in DMSO (0.57 mL, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (13 mg, 13 mol, 2.5 mol %) was added and the mixture was stirred at rt under oxygen atmosphere (1 atm). The reaction stopped after 43 h at 69% conversion as indicated by .sup.1H-NMR.

(33) Tert-butyl peroxybenzoate (DMSO as Solvent)

(34) Methyl--glucopyranoside (30 mg, 0.15 mmol, 1.0 eq) and tert-butyl peroxybenzoate (74 L, 0.46 mmol, 3.0 eq) were dissolved in DMSO (0.17 mL, 0.9 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (4 mg, 3.8 mol, 2.5 mol %) was added and the mixture was stirred at rt. The reaction stopped after 13 days at 67% conversion as indicated by .sup.1H-NMR.

(35) Air (Oxygen) as Oxidant (DMSO as Solvent)

(36) Methyl--glucopyranoside (30 mg, 0.15 mmol, 1.0 eq) was dissolved in DMSO (0.5 mL, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (4 mg, 3.8 mol, 2.5 mol %) was added. The mixture was stirred at rt with a gentle stream of air. The reaction stopped after 13 days at 73% conversion as indicated by .sup.1H-NMR.

(37) Cumene Hydroperoxide as Oxidants (DMSO as Solvent)

(38) Methyl--glucopyranoside (30 mg, 0.15 mmol, 1.0 eq) and cumene hydroperoxide (86 L, 0.46 mmol, 3.0 eq) were dissolved in DMSO (0.5 mL, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (4 mg, 3.8 mol, 2.5 mol %) was added and the mixture was stirred at rt. The reaction stopped after 13 days at 69% conversion as indicated by .sup.1H-NMR.

(39) Hydrogen Peroxide as Oxidants (DMSO as Solvent)

(40) Methyl--glucopyranoside (30 mg, 0.15 mmol, 1.0 eq) and hydrogen peroxide 30% (46 L, 0.46 mmol, 3.0 eq) were dissolved in DMSO (0.5 mL, 0.3 M). The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (4 mg, 3.8 mol, 2.5 mol %) was added and the mixture was stirred at rt. The reaction showed 49% conversion after 16 days as indicated by .sup.1H-NMR.

Example 10

Reduction of the Mono-Oxidized Carbohydrates

(41) Methyl--allopyranoside

(42) ##STR00010##

(43) was dissolved in MeOH (8.5 mL) and the mixture was cooled to 0 C. Sodium borohydride (118 mg, 3.12 mmol, 3.0 eq) was added and the mixture stirred for 30 min at rt. Excess borohydride was destroyed by addition of acidic ion exchange resin (Amberlite 120 H.sup.+-form), the mixture was filtered over celite and concentrated in vacuo. The residue was co-evaporated with MeOH (310 mL) to give 193 mg (0.99 mmol, 95%) of methyl--allopyranoside as reddish sticky oil.

(44) .sup.1H NMR.sup.[3] (400 MHz, CD.sub.3OD): =4.69 (d, J=3.8 Hz, 1H), 3.98 (appears as t, J=3.2 Hz, 1H), 3.88-3.82 (m, 1H), 3.74-3.67 (m, 2H), 3.60 (appears as t, J=3.6 Hz, 1H), 3.47 (dd, J=9.7, 3.1 Hz, 1H), 3.43 (s, 3H). .sup.13C NMR (101 MHz, CD.sub.3OD) =101.6, 73.6, 69.6, 69.1, 68.4, 62.8, 56.2. HRMS (ESI) calculated for C.sub.7H.sub.14O.sub.6Na ([M+Na].sup.+): 217.0683. found: 217.0682.

Example 11

Oximation of the Mono-Oxidized Carbohydrate

(45) A. E/Z-Methyl-3-O-methyloxime--D-ribo-hexapyranoside

(46) ##STR00011##

(47) Methyl--D-ribo-hexapyranosid-3-ulose (330 mg, 1.70 mmol, 1.0 eq), O-methylhydroxylamine hydrochloride (215 mg, 2.58 mmol, 1.5 eq) and NaHCO.sub.3 (218 mg, 2.58 mmol, 1.5 eq) were heated at reflux for 2 h in methanol (13 mL). After filtration to remove salts, and evaporation of the solvent, the residue was extracted with hot ethyl acetate. The extract was passed over a short silica gel column and was concentrated in vacuo, to give methyl-3-O-methyloxime--D-ribo-hexapyranoside (344 mg, 1.55 mmol, 92% as a mixture of E/Z isomers) as a sticky yellow solid. HRMS (ESI) exact mass calculated for C.sub.8H.sub.15NO.sub.6H ([M+H].sup.+): 222.0972. found: 222.0970, C.sub.9H.sub.15O.sub.6Na ([M+Na].sup.+): 244.0792. found: 244.0789 IR .sub.max/cm.sup.1: 3454 (OH), 2946 (CH), 1034 (CO).

(48) B. E/Z-Methyl-3-O-methyloxime--D-ribo-hexapyranoside

(49) ##STR00012##

(50) Methyl--D-ribo-hexapyranosid-3-ulose (300 mg, 1.56 mmol, 1.0 eq), O-methylhydroxylamine hydrochloride (195 mg, 2.34 mmol, 1.5 eq) and NaHCO.sub.3 (197 mg, 2.34 mmol, 1.5 eq) in methanol (13 mL) were heated at reflux for 2.5 h. After filtration to remove salts and evaporation of the solvent, the residue was extracted with hot ethyl acetate and the extract was passed over a short silica gel column. Removing the solvent in vacuo gave methyl-3-O-methyloxime--D-ribo-hexapyranoside (311 mg, 1.41 mmol, 90% as a mixture of E/Z isomers) as a sticky yellow solid. HRMS (ESI) exact mass calculated for C.sub.8H.sub.15NO.sub.6H ([M+H].sup.+): 222.0972. found: 222.0970, C.sub.9H.sub.15O.sub.6Na ([M+Na].sup.+): 244.0792. found: 244.0789 IR .sub.max/cm.sup.1: 3447 (OH), 2946 (CH), 1031 (CO).

(51) C. E/Z-Methyl-2-(acetamido)-2-desoxy-3-O-methyloxime--D-ribo-hexapyranoside

(52) ##STR00013##

(53) 2-(acetamino)-2-desoxy--D-ribo-hexapyranosid-3-ulose (300 mg, 1.37 mmol, 1.0 eq), O-methylhydroxylamine hydrochloride (171 mg, 2.05 mmol, 1.5 eq) and NaHCO.sub.3 (172 mg, 2.05 mmol, 1.5 eq) in methanol (12 mL) were heated under reflux for 3 h. After filtration to remove salts and evaporation of the solvent, the residue was extracted with hot ethyl acetate and the extract was passed over a short silica gel column and was concentrated in vacuo, to give methyl-2-(acetamido)-2-desoxy-3-O-methyloxime--D-ribo-hexapyranoside (308 mg, 1.17 mmol, 86% as a mixture of E/Z isomers) as a sticky yellow solid. HRMS (ESI) exact mass calculated for C.sub.10H.sub.18N.sub.2O.sub.6H ([M+H].sup.+): 263.1238. found: 263.1235, C.sub.10H.sub.18N.sub.2O.sub.6Na ([M+Na].sup.+): 285.1057. found: 285.1054 IR .sub.max/cm.sup.1: 3447 (OH), 2946 (CH), 1654 (OCN), 1031 (CO).

Example 12

Synthesis of Methyl-3-amino--D-ribo-hexapyranoside

(54) ##STR00014##

(55) E/Z-Methyl-3-O-methyloxime--D-ribo-hexapyranoside (Example 11A; 240 mg, 1.08 mmol, 1.0 eq) in acetic acid (5 mL) was hydrogenated over platinum(IV) oxide (25 mg, 0.11 mmol, 10 mol %) under hydrogen pressure (5 bar) for 24 h. The mixture was passed over a short celite column and concentrated in vacuo, to give methyl-3-amino--D-ribo-hexapyranoside (208 mg, 1.08 mmol, 99%) as a sticky slightly yellow solid. The product was directly used in a subsequent per-acetylation reaction. .sup.1H NMR (400 MHz, 298 K, DMSO-d.sub.6): =5.21 (d, J=3.1 Hz, 1H), 4.31-4.26 (m, 2H), 4.23 (dd, J=9.9, 4.1 Hz, 1H), 4.15 (dd, J=11.0, 4.9 Hz, 2H), 4.00 (d, J=4.2 Hz, 1H), 3.90 (s, 3H).

Example 13

Synthesis of Methyl-3-acetamido-2,4,6-tri-O-acetyl-3-deoxy--D-ribo-hexapyranoside

(56) ##STR00015##

(57) Methyl-3-amino--D-ribo-hexapyranosid (Example 12; 208 mg, 1.08 mmol, 1.0 eq) was dissolved in dry pyridine (2.4 mL) and acetic anhydride (1 mL, 9.9 mmol, 8 eq). The reaction mixture was stirred overnight. The mixture was co-evaporated with toluene (1 mL) and purified by automated silicagel column chromatography (GRACE) with a solvent gradient of pentane/EtOAc (1:1 to pure EtOAc) to give methyl-3-acetamido-2,4,6-tri-O-acetyl-3-deoxy--D-ribo-hexapyranoside (245 mg, 63%, 0.68 mmol) as a white solid. .sup.1H NMR.sup.[5] (400 MHz, 298 K, DMSO-d.sub.6): =7.11 (d, J=8.7 Hz, 1H), 4.81 (d, J=3.2 Hz, 1H), 4.79-4.76 (m, 1H), 4.73 (d, J=9.3 Hz, 2H), 4.15 (d, J=3.3 Hz, 2H), 4.10 (dd, J=9.0, 3.4 Hz, 1H), 3.30 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H).

Example 14

Synthesis of Methyl-3-acetamido--D-ribo-hexapyranoside

(58) ##STR00016##

(59) Methyl-3-acetamido-2,4,6-tri-O-acetyl-3-deoxy--D-ribo-hexapyranoside (Example 13; 141 mg, 0.39 mmol, 1.0 eq) was dissolved in dry methanol (1.4 mL). To this mixture, sodium methanolate (1 M, 0.1 mL) was added and the reaction mixture was stirred overnight at rt upon which the reaction had finished as indicated by TLC (pentane/EtOAc 1:1). The reaction was quenched with acidic ion exchange resin (Amberlite 120 H.sup.+-form) and stirred for an additional 10 min. After passing over a short silica gel column, the solvent was removed in vacuo to give methyl-3-amido--D-ribo-hexapyranoside (90 mg, 99%, 0.38 mmol) as a sticky slightly red solid. .sup.1H NMR (400 MHz, 298 K, DMSO-d.sub.6): =6.71 (d, J=8.9 Hz, 1H, NH), 4.52 (d, J=3.0 Hz, 1H, 1-H), 4.38-4.30 (m, 1H, 3-H), 3.63 (dd, J=11.4, J=1.6 Hz, 1H, 6-H), 3.56 (dd, J=5.2, 2.7 Hz, 1H, 2-H), 3.46 (m, 1H, 6-H), 3.43 (m, 2H, 4-H, 5-H), 3.32 (s, 3H, OCH.sub.3), 1.88 (s, 3H, CH.sub.3). .sup.13C NMR (101 MHz, 298 K, DMSO-d.sub.6): =170.9 (NHCOCH.sub.3), 99.6 (CH, C-1), 68.8 (CH, C-4), 66.3 (CH, C-2), 66.0 (CH, 5-C), 60.7 (CH.sub.2, C-6), 54.8 (OCH.sub.3), 52.8 (CH, C-3), 23.6 (NHCOCH.sub.3). gCOSY (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.1H)=6.71/4.34 (NH/3-H), 4.52/3.56 (1-H/2-H), 4.38-4.30/6.71, 3.56, 3.43 (3-H/NH, 2-H, 4-H), 3.63/3.46, 3.43 (6-H/6-H, 5-H), 3.56/4.52, 4.34 (2-H/1-H, 3-H), 3.46/3.63, 3.43 (6-H/6-H, 5-H), 3.43/4.34, 3.43 (4-H/3-H, 5-H), 3.43/3.63, 3.46 (5-H/6-H, 6-H). gHSQC (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.13C)=4.52/99.63 (1-H/C-1), 4.38-4.30/52.75 (3-H, C-3), 3.63/60.73 (6-H/C-6), 3.56/66.34 (2-H/C-2), 3.46/60.73 (6-H/C-6), 3.43/68.83 (4-H/C-4), 3.43/66.00 (5-H/C-5), 3.32/23.58 (OCH.sub.3/OCH.sub.3), 1.88/54.81 (CH.sub.3/CH.sub.3). NOESY (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.1H)=3.43/3.63, 3.56 (4-H/6-H, 2-H), 3.43/6.71, 1.88 (5-H/NH, CH.sub.3). HRMS (ESI) calculated for C.sub.9H.sub.17NO.sub.6H ([M+H].sup.+): 236.1129. found: 236.1127, C.sub.9H.sub.17NO.sub.6Na ([M+Na].sup.+): 258.0948. found: 258.0947.

Example 15

Synthesis of Methyl-3-amino--D-ribo-hexapyranoside

(60) ##STR00017##

(61) Methyl-3-O-methyloxime--D-ribo-hexapyranoside (Example 11B; 299 mg, 1.14 mmol, 1.0 eq) in acetic acid (5 mL) was hydrogenated over platinum(IV) oxide (26 mg, 0.14 mmol, 10 mol %) under hydrogen pressure (5 bar). The mixture was passed over a short celite column and was concentrated in vacuo, to give methyl-3-amino--D-ribo-hexapyranoside (267 mg, 1.14 mmol, 99%) as a sticky slightly yellow solid. The product was directly used in a subsequent per-acetylation reaction (Example 16) to separate diastereomers. .sup.1H NMR.sup.[5] (400 MHz, 298 K, DMSO-d.sub.6): =4.46 (d, J=7.6 Hz, 1H), 3.66-3.61 (m, 1H), 3.60-3.52 (m, 2H), 3.45 (dd, J=11.6, 5.0 Hz, 1H), 3.40 (d, J=3.3 Hz, 1H), 3.37 (s, 3H), 3.33 (dd, J=7.3, 4.2 Hz, 1H).

Example 16

Synthesis of Methyl-3-acetamido-2,4,6-tri-O-acetyl-3-deoxy--D-ribo-hexapyranoside

(62) ##STR00018##

(63) Methyl-3-amino--D-ribo-hexapyranoside (Example 15; 272 mg, 1.41 mmol, 1.0 eq) was dissolved in dry pyridine (2.8 mL) and acetic anhydride (1 mL, 11 mmol, 8 eq). The reaction mixture was stirred overnight and subsequently co-evaporated with toluene (1 mL) in vacuo, to give methyl-3-acetamido-2,4,6-tri-O-acetyl-3-deoxy--D-ribo-hexapyranoside as a white solid. The crude product was purified and the two diastereomers were separated by automatic silica gel column chromatography (GRACE) with a solvent gradient of pentane/EtOAc. 15 mg (3%) of pure C3-NHAc.sub.aq and 49 mg (10%) of C3-NHAc.sub.ax could be isolated along with 254 mg of mixed fractions (318 mg, 63%, 0.88 mmol). C3-NHAc.sub.ax: .sup.1H NMR.sup.[5] (400 MHz, 298 K, DMSO-d.sub.6): =7.93 (d, J=9.6 Hz, 1H, NH), 4.80 (d, J=8.2 Hz, 1H, 1-H), 4.76 (dd, J=9.4, 4.6 Hz, 1H, 3-H), 4.70 (dd, J=9.1, 4.2 Hz, 1H, 4-H), 4.55 (dd, J=7.9, 4.6 Hz, 1H, 2-H), 4.20-4.10 (m, 3H, 5-H, 6-H, 6-H), 3.39 (s, 3H, OCH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.96 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3). .sup.13C NMR (101 MHz, 298 K, DMSO-d.sub.6): =170.4 (COCH.sub.3), 170.1 (COCH.sub.3), 169.2 (COCH.sub.3), 169.1 (COCH.sub.3), 98.2 (CH, C-1), 69.7 (CH, C-5), 69.1 (CH, C-2), 66.3 (CH, C-4), 62.5 (CH.sub.2, C-6), 55.9 (OCH.sub.3), 46.0 (CH, C-3), 22.5 (NHCOCH.sub.3), 20.6 (COCH.sub.3), 20.5 (COCH.sub.3), 20.5 (COCH.sub.3). gCOSY (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.1H)=7.93/4.76 (NH/3-H), 4.80/4.55 (1-H/2-H), 4.76/7.93, 4.70, 4.55 (3-H/NH, 4-H, 2-H), 4.70/4.76, 4.16 (4-H/3-H, 5-H), 4.55/4.80, 4.76 (2-H/1-H, 3-H), 4.16/4.70, 4.16 (5-H/4-H, 6-H, 6-H), 4.16/4.16 (6-H, 6-H/5-H). gHSQC (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.13C)=4.80/98.20 (1-H, C-1), 4.76/46.01 (3-H/C-3), 4.70/66.34 (4-H/C-4), 4.55/69.12 (2-H/C-2), 4.16/69.71, 62.48 (5-H, 6-H, 6-H/C-5, C-6) HRMS (ESI) calculated for C.sub.15H.sub.23NO.sub.9H ([M+H].sup.+): 326.1446. found: 326.1443, C.sub.15H.sub.23NO.sub.9Na ([M+Na].sup.+): 384.1265. found: 384.1261.

(64) C3-NHAc.sub.eq: .sup.1H NMR (400 MHz, 298 K, DMSO-d.sub.6): =7.94 (d, J=9.3 Hz, 1H, NH), 4.80 (dd, J=10.0 Hz, 10.0 Hz, 1H, 4-H), 4.70 (dd, J=10.5 Hz, 8.3 Hz, 1H, 2-H), 4.59 (d, J=7.8 Hz, 1H, 1-H), 4.19 (ddd, J=10.6 Hz, 10.0 Hz, 9.3 Hz, 1H, 3-H), 4.13 (m, 1H), 3.99 (m, 1H), 3.88 (ddd, J=10.0, 9.4, 3.1 Hz, 1H, 5-H), 3.36 (s, 3H, OCH.sub.3), 2.01 (s, 3H, CH.sub.3), 1.96 (s, 6H, CH.sub.3), 1.71 (s, 3H, CH.sub.3). .sup.13C NMR (101 MHz, 298 K, DMSO-d.sub.6): =170.1 (NHCOCH.sub.3), 169.4 (2 COCH.sub.3), 169.0 (COCH.sub.3), 101.2 (CH, C-1), 71.8 (CH, C-5), 71.2 (CH, C-2), 68.6 (CH, C-4), 62.1 (CH.sub.2, C-6), 56.2 (OCH.sub.3), 52.0 (CH, C-3), 22.6 (NHCOCH.sub.3), 20.6 (COCH.sub.3), 20.5 (COCH.sub.3), 20.4 (COCH.sub.3). gCOSY (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.1H)=7.94/4.19 (NH/3-H), 4.80/4.19, 3.88 (4-H/3-H, 5-H), 4.70/4.59, 4.19 (2-H/1-H, 3-H), 4.59/4.70 (1-H, 2-H), 4.19/7.94, 4.80, 4.70 (3-H/NH, 4-H, 2-H), 4.13/3.99, 3.88 (CH.sub.2/5-H, CH.sub.2), 3.99/4.13, 3.88 (CH.sub.2/CH.sub.2, 5-H), 3.88/4.80, 4.13, 3.99 (5-H/4-H, CH.sub.2, CH.sub.2). gHSQC (400 MHz, 298 K, DMSO-d.sub.6): (.sup.1H)/ (.sup.13C)=4.80/68.59 (4-H/C-4), 4.70/71.19 (2-H, C-2), 4.59/101.25 (1-H, C-1), 4.19/51.99 (3-H/C-3), 4.13/62.08 (CH.sub.2/C-6), 3.99/62.08 (CH.sub.2/C-6), 3.88/71.83 (5-H/C-5) HRMS (ESI) calculated C.sub.15H.sub.23NO.sub.9H ([M+H].sup.+): 326.1446. found: 326.1442, C.sub.15H.sub.23NO.sub.9Na ([M+Na].sup.+): 384.1265. found: 384.1261.

Example 17

Oxidation of Neomycin B

(65) ##STR00019##

(66) Carboxybenzyl (Cbz)-protected Neomycin B (190 mg, 134 mol, 1.0 eq) and 2,6 dichlorobenzoquinone (71.1 mg, 402 mol, 3.0 eq) were dissolved in 446 L DMSO. [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)]2(OTf)2 (1.5 mg, 1.5 mol 1.1 mol %) was added and the mixture was stirred over night. Water (5 mL) was added and the mixture was freeze-dried over night. Pure oxidized Cbz-protected Neomycin B (41 mg, 22%) was isolated after purification by column chromatography (eluent: gradient of DCM/MeOH 0-10%) along with mixed fractions. HRMS (ESI) calculated for C.sub.71H.sub.81N.sub.6O.sub.25 ([M+H].sup.+): 1417.5246. found: 1417.5122, C.sub.71H.sub.80N.sub.6O.sub.25Na ([M+Na].sup.+): 1439.5065. found: 1439.4911.

(67) ##STR00020##

Example 18

Oxidation Using BIAN-Complexes

(68) Methyl--D-glucopyranoside (30 mg, 0.15 mmol, 1.0 eq) and benzoquinone (50 mg, 0.46 mmol, 3.0 eq) were dissolved in a dioxane/DMSO mixture (4:1, 0.5 mL, 0.3 M). (Bis[N-(2,6-dimethylphenyl)imino]acenaphthene)-Pd-(OAc)2 (1.2 mg, 1.9 gmol, 1.25 mol %) and [(bis[N-(2,6-dimethylphenyl)imino]acenaphthene)-Pd-(CH3CN)2](OTf)2 (1.2 mg, 1.9 gmol, 1.25 mol %) were added. After the reaction was stirred over night at 60 C., NMR-spectroscopy showed conversion of 9% to the methyl--D-ribohexapyranosid-3-ulose (oxidation on C3) as single product.

Example 19

Oxidation of methyl-2-desoxy--glucopyranoside

(69) ##STR00021##

(70) Methyl-2-desoxy--glucopyranoside (150 mg, 0.84 mmol, 1.0 eq) and 2,6-dichloro-1,4-benzoquinone (447 mg, 2.53 mmol, 3.0 eq) were dissolved in 2.5 mL dioxane/DMSO mixture (4:1, 0.3 M) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (22 mg, 2.5 mol %) was added. The mixture was stirred at rt for 30 min. The reaction was quenched by adding water (12 mL) and the resulting precipitate was filtered. The filter was washed with 32.25 mL of water and the combined water layers were passed over a charcoal column (12 g of charcoal). The charcoal column was washed with 4 column volumes of water and subsequently the product was eluted with water/acetonitrile 1:1 (2.5 column volumes). Methyl-2-deoxy--D-erythro-hexopyranosid-3-ulose (89 mg, 0.50 mmol, 60%) was obtained pure, after freeze drying, as greenish oil. .sup.1H NMR (400 MHz, CD.sub.3OD): 5.14 (d, J=4.3 Hz, 1H), 4.18 (dd, J=9.9, 1.1 Hz, 1H), 3.88 (dd, J=12.0, 2.3 Hz, 1H), 3.81 (dd, J=12.0, 4.7 Hz, 1H), 3.69 (ddd, J=9.9, 4.7, 2.3 Hz, 1H), 3.34 (s, 3H), 2.88 (ddd, J=14.1, 4.5, 1.1 Hz, 1H), 2.50 (dd, J=14.1, 1.1 Hz, 1H). .sup.13C NMR (101 MHz, CD.sub.3OD): 207.39 (C.sub.quart.), 101.34 (CH), 76.53 (CH), 74.27 (CH), 62.79 (CH.sub.2), 55.18 (CH.sub.3), 46.80 (CH.sub.2). HRMS (APCI) calculated for C.sub.7H.sub.13O.sub.5 ([M+H].sup.+): 177.076. found: 177.075.

Example 20

Synthesis of phenyl--D-ribo-hexapyranoside-3-ulose

(71) ##STR00022##

(72) Phenyl--D-glucopyranoside (108 mg, 0.42 mmol, 1.0 eq) was dissolved in a dioxane/DMSO mixture (4:1, 1.3 mL, 0.32 M) and dichlorobenzoquinone (223 mg, 1.26 mmol, 3.0 eq) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (11 mg, 2.5 mol %) were added. The reaction was stirred for 30 min and was quenched by addition of 8 mL water. The mixture was filtered and the precipitates were washed with water (32 mL). The water layer was concentrated using a Genevac (T<40 C.), which gave 230 mg of crude product. The crude product was purified by column chromatography (21 g silica gel (SG2), eluent: DCM/MeOH 20/1, DCM was saturated with water), which gave 89 mg (contains about 13% DMSO according to .sup.1H-NMR, 0.30 mmol, 73%) of pure phenyl--D-ribo-hexapyranoside-3-ulose. .sup.1H NMR (400 MHz, CD.sub.3OD): =7.29 (t, J=7.9 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 5.83 (d, J=4.2 Hz, 1H), 4.58 (dd, J=4.2, 1.1 Hz, 1H), 4.38 (dd, J=9.0, 1.1 Hz, 1H), 3.85-3.74 (m, 3H). .sup.13C NMR (101 MHz, CD.sub.3OD): =206.9 (C.sub.quart.), 158.2 (C.sub.quart.), 130.7 (CH), 124.0 (CH), 118.2 (CH), 101.9 (CH), 77.7 (CH), 76.0 (CH), 73.3 (CH), 62.3 (CH.sub.2). HRMS (ESI) calculated for C.sub.12H.sub.14O.sub.6Na ([M+Na].sup.+): 277.068. found: 277.068.

Example 21

Synthesis of thiophenyl--D-ribo-hexopyranoside-3-ulose

(73) ##STR00023##

(74) Phenylthio--glucopyranoside (229 mg, 0.84 mmol, 1.0 eq) and 2,6-dichloro-1,4-benzoquinone (446 mg, 2.53 mmol, 3.0 eq) were dissolved in 2.8 mL dioxane/DMSO mixture (4:1, 0.3 M) and [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 was added portions wise over time (6.5 mol %, 57.2 mg 54.6 gmol in total, 41 mol % every 2 h then 21.0 mol % every 1 h and 10.5 mol % after 1 h). The mixture was stirred at rt for additional 1 h (12 h in total), no more starting material was observed by NMR-spectroscopy. The reaction was quenched by adding water (17 mL) and the resulting precipitate was filtered. The filter was washed with 32 mL of water and the combined water layers were passed over a charcoal column chromatography (10 g charcoal). The charcoal column was washed with 6 column volumes of water and subsequently with acetonitrile/water mixtures (25%, 50%, 75%, 100% acetonitrile, 200 ml each, 50% acetonitrile eluted the product) to elute the product. The fractions containing the product were freeze dried to give 107 mg (0.39 mmol, 47%) of pure product as white fluffy solid. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.64-7.49 (m, 2H), 7.37-7.20 (m, 3H), 4.68 (d, J=10.0, 1H), 4.24 (dd, J=10.1, 1.4 Hz, 1H), 4.06 (dd, J=10.0, 1.4 Hz, 1H), 3.93 (dd, J=12.3, 2.0 Hz, 1H), 3.79 (dd, J=12.3, 4.9 Hz, 1H), 3.43 (ddd, J=10.1, 4.9, 2.0 Hz, 1H). .sup.13C NMR (101 MHz, CD.sub.3OD): =207.4, 134.0, 133.9, 130.1, 129.1, 91.0, 84.0, 76.1, 73.9, 62.8. HRMS (ESI) calculated for C.sub.12H.sub.14O.sub.5SNa ([M+Na].sup.+): 293.045. found: 293.045.

Example 22

Oxidation of Methylallose

(75) ##STR00024##

(76) Methyl-allose (74 mg, 0.38 mmol, 1 eq) and 2,6-Dichlorobenzoquinone (202 mg, 1.14 mmol, 3 eq) were dissolved in 1.3 mL Acetonitril/water (10:1) mixture.). [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (10 mg, 9.5 mol, 2.5 mol %) was added and the mixture was stirred at r.t. for 6 h. The reaction mixture was diluted with 1 mL water and was washed with 10 mL toluene. The water layer was washed with 5 mL ether. The water layer was filtered and concentrated to give a 3.6/1 mixture of oxidation on C2/C3 according to NMR, thus demonstrating the regioselectivity.

Example 23

Oxidation of myo-inositol

(77) ##STR00025##

(78) Myo-inositol (50 mg, 0.28 mmol, 1 eq) and 2,6-dichlorobenzoquinone (147 mg, 0.83 mmol, 3 eq) were dissolved in DMSO (0.9 mL). [(2,9-dimethyl-1,10-phenanthroline)-Pd(-OAc)].sub.2(OTf).sub.2 (7 mg, 7 gmol, 2.5 mol %) was added and the mixture was stirred at r.t. for 4.5 h. Reaction mixture was diluted with 1 mL water and was washed with 10 mL toluene and with 5 mL ether. The water layer was filtered and concentrated to give a 3:1 mixture of two oxidation products according to NMR.

REFERENCES

(79) [1] For NMR-spectrum in D.sub.2O see: G. de Wit, C. de Hann, A. P. G. Kieboom, H. van Bekkum, Carbohydr. Res. 1980, 86, 33-41. [2] For NMR-spectrum in D.sub.2O see: S. Freimund, A. Huwig, F. Giffhorn, S. Kpper, Chem. Eur. J. 1998, 4, 2442-2455. [3] For NMR-spectrum in D.sub.2O see: J. S. Brimacombe, A. Husain, Carbohydr. Res. 1968, 6, 491-493. [4] For NMR-spectrum in D.sub.2O see: C. H. Wong, Y. Ichikawa, T. Krach, C. Gautheron-Le Narvor, D. P. Dumas, G. C. Look, J. Am. Chem. Soc. 1991, 113, 8137-8145. [5] For NMR-spectrum in D.sub.2O or CDCl.sub.3 see: H. H. Baer, Y. Gan, Carbohydr. Res. 1991, 210, 233-245.